A key challenge in moving from a genetic understanding of disease to effective therapeutics is the[unreadable] identification of functionally validated effectors of the process, against which small molecule inhibitors can be[unreadable] developed. The challenge in the case of acute lymphoblastic leukemia (ALL) is that such effectors are not[unreadable] known. The drug discovery challenge in ALL is compounded by the fact that ALL does not represent an[unreadable] attractive market for industry, thus shifting the burden of early chemical discovery to academia. We propose[unreadable] here a chemical genomic solution whereby a small molecule screen is performed based on the ability of[unreadable] compounds to modulate a gene expression program of interest. This is based on our recently reported Gene[unreadable] Expression-Based High Throughput Screening (GE-HTS) method wherein we demonstrated that we could identify small molecules capable of inducing myeloid differentiation[unreadable] of AML cells based on their ability to trigger a gene expression signature of interest. We now propose to[unreadable] extend this approach to three important areas of ALL biology. In Aim 1, we will define a gene expression[unreadable] signature of TEL/AML1 activity, and we will attempt to identify compounds capable of reversing the[unreadable] TEL/AML1 gene expression program. Such compounds would be a starting point for molecularly targeted[unreadable] therapy for TEL/AML1 positive patients. In Aim 2, we will similarly attempt to identify compounds capable of[unreadable] reversing the molecular program of MLL mutation as a means of exploring therapeutic approaches for MLL-rearranged[unreadable] leukemias. Lastly, in Aim 3 we will screen for chemicals capable of modulating glucocorticoid[unreadable] sensitivity in ALL cells. Such molecules would have great utility both as biological tool compounds with[unreadable] which to better understand the biology of glucocorticoid sensitivity, and may also suggest therapeutic[unreadable] strategies for ALL patients unlikely to respond to standard therapy.